Anticholinergic burden measures, symptoms, and fall-associated risk in older adults with polypharmacy: Development and validation of a prognostic model.

BACKGROUND: Anticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls. To account for patients' individual susceptibility to medications, the added predictive value of typical anticholinergic symptoms was further quantified in this context. METHODS AND FINDINGS: To predict falls, models were developed and validated based on logistic regression models created using data from two German cluster-randomized controlled trials. The outcome was defined as "≥ 1 fall" vs. "no fall" within a 6-month follow-up period. Data from the RIME study (n = 1,197) were used in model development, and from PRIMUM (n = 502) for external validation. The models were developed step-wise in order to quantify the predictive ability of anticholinergic burden measures, and anticholinergic symptoms. In the development set, 1,015 patients had complete data and 188 (18.5%) experienced ≥ 1 fall within the 6-month follow-up period. The overall predictive value of the five anticholinergic measures was limited, with neither the employed anticholinergic variable (binary / count / burden), nor dose-dependent or dose-independent measures differing significantly in their ability to predict falls. The highest c-statistic was obtained using the German Anticholinergic Burden Score (0.73), whereby the optimism-corrected c-statistic was 0.71 after interval validation using bootstrapping and 0.63 in the external validation. Previous falls and dizziness / vertigo had the strongest prognostic value in all models. CONCLUSIONS: The ability of anticholinergic burden measures to predict falls does not appear to differ significantly, and the added value they contribute to risk classification in fall-prediction models is limited. Previous falls and dizziness / vertigo contributed most to model performance.

Vericiguat in Combination with Short-Acting Nitroglycerin in Patients With Chronic Coronary Syndromes: The Randomized, Phase Ib, VENICE Study.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults with symptomatic chronic HF and ejection fraction less than 45%. Guidelines recommend short-acting nitrates, such as sublingual nitroglycerin, for the treatment of acute angina pectoris in patients with chronic coronary syndromes (CCSs), common comorbidities in HF. We evaluated safety, tolerability, and the pharmacodynamic interaction between vericiguat and nitroglycerin, coadministered in patients with CCSs. In this phase Ib, double-blind, randomized, multicenter study, 36 patients with CCSs received either vericiguat 2.5 mg (up-titrated every 2 weeks to 5 mg and 10 mg) or placebo. Patients also received nitroglycerin (0.4 mg sublingual). In total, 31 patients completed the study (vericiguat + nitroglycerin, n = 21; placebo + nitroglycerin, n = 10). There was no increase in treatment-emergent adverse events (TEAEs) with vericiguat + nitroglycerin vs. placebo + nitroglycerin; three patients discontinued due to TEAEs (vericiguat + nitroglycerin, n = 1; placebo + nitroglycerin, n = 2). Decreases in mean blood pressure (BP; 6-10 mmHg systolic BP (SBP); 4-6 mmHg diastolic BP (DBP)) were independent of vericiguat exposure and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and placebo. Coadministration of vericiguat with nitroglycerin in patients with CCSs was well tolerated, and the combination is unlikely to cause significant adverse effects beyond those known for nitroglycerin.

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

Drug-induced blood consumption: the impact of adverse drug reactions on demand for blood components in German departments of internal medicine.

Therapy for adverse drug reactions (ADRs) often results in the application of blood components. This study aims to assess the demand for blood components and the resulting economic burden (hospital perspective) in German hospitals induced by ADRs leading to admissions to departments of internal medicine. In this prospective study, ADRs leading to hospitalization were surveyed in four regional pharmacovigilance centres in Germany during the years 2000-2007. ADRs assessed as 'possible', 'likely' or 'very likely' were included. Market prices for blood components and hospitalization data were determined by desktop research. A probabilistic sensitivity analysis was performed. A total of 6099 patients were admitted to internal medicine departments because of an outpatient ADR of whom 1165 patients (19.1%; mean age, 73.0 ± 13.0 years) required treatment with blood components owing to major bleeding events. Overall consumption was 4185 erythrocyte concentrates (EC), 426 fresh frozen plasma (FFP) and 48 thrombocyte (TC) units. On the basis of statistical hospital data, we estimated a nationwide demand of approximately 132,020 EC, 13,440 FFP and 1515 TC units, resulting in total costs of €12.66 million per year for all German hospitals. Some 19.2% of all ADR cases were assessed as preventable. Theoretically, a nationwide decreased demand for blood components and a savings potential of €2.43 million per year could be achieved by preventing ADRs in Germany. Blood components are used in one-fifth (mainly gastrointestinal bleeding) of all ADRs, leading to hospitalizations in internal medicine departments. Both blood demand and hospital procurement costs can be significantly lowered by preventing ADRs.

Adverse drug reactions in Germany: direct costs of internal medicine hospitalizations.

PURPOSE: German hospital reimbursement modalities changed as a result of the introduction of Diagnosis Related Groups (DRG) in 2004. Therefore, no data on the direct costs of adverse drug reactions (ADRs) resulting in admissions to departments of internal medicine are available. The objective was to quantify the ADR-related economic burden (direct costs) of hospitalizations in internal medicine wards in Germany. METHODS: Record-based study analyzing the patient records of about 57,000 hospitalizations between 2006 and 2007 of the Net of Regional Pharmacovigilance Centers (Germany). All ADRs were evaluated by a team of experts in pharmacovigilance for severity, causality, and preventability. The calculation of accurate person-related costs for ADRs relied on the German DRG system (G-DRG 2009). Descriptive and bootstrap statistical methods were applied for data analysis. RESULTS: The incidence of hospitalization due to at least 'possible' serious outpatient ADRs was estimated to be approximately 3.25%. Mean age of the 1834 patients was 71.0 years (SD 14.7). Most frequent ADRs were gastrointestinal hemorrhage (n = 336) and drug-induced hypoglycemia (n = 270). Average inpatient length-of-stay was 9.3 days (SD 7.1). Average treatment costs of a single ADR were estimated to be approximately €2250. The total costs sum to €434 million per year for Germany. Considering the proportion of preventable cases (20.1%), this equals a saving potential of €87 million per year. CONCLUSIONS: Preventing ADRs is advisable in order to realize significant nationwide savings potential. Our cost estimates provide a reliable benchmark as they were calculated based on an intensified ADR surveillance and an accurate person-related cost application.

Detection of adverse drug reactions in a neurological department: comparison between intensified surveillance and a computer-assisted approach.

OBJECTIVES: Adverse drug reactions (ADRs) leading to hospitalisation or occurring during hospital stay contribute significantly to patient morbidity and mortality as well as representing an additional cost for healthcare systems. The aim of this study was to provide data about the type and incidence of ADRs in a neurological department and to compare two different methodological approaches to collecting information on ADRs. METHODS: The two methods used were intensified surveillance of neurological wards by daily ward rounds and computer-assisted screening for ADRs by means of pathological laboratory parameters. RESULTS: Of admissions to the neurological department, 2.7% were caused by an ADR and 18.7% of patients experienced at least one ADR during hospitalisation. The positive predictive values of pathological laboratory parameters ranged between 0% (eosinophil count) and 100% for increased drug serum concentrations and international normalised ratio, i.e. the latter were always accompanied by a clinically relevant ADR. However, only half of all ADR could be detected by pathological laboratory parameters, the sensitivity of this method came to 45.1% with a specificity of 78.9%. CONCLUSION: Similar to departments of internal medicine, a high number of ADRs occur on neurological wards. The predominant ADRs were those typical of neurotropic medications such as dyskinesia and increased sedation. Due to the age of the patients involved, cardiovascular co-medication is often prescribed and represents an additional risk factor for ADRs. By measuring pathological laboratory parameters the majority of ADRs could not be detected in neurological patients.